Abuse-proofed dosage form

ABSTRACT

An abuse-proofed, thermoformed dosage form containing, in addition to one or more active ingredients with abuse potential optionally together with physiologically acceptable auxiliary substances, at least one synthetic or natural polymer with a breaking strength of at least 500 N and to a process for the production thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. patent application Ser. No.10/718,112, filed Nov. 20, 2003, now allowed, which claims priority ofGerman Patent Application No. 103 36 400.5, filed Aug. 6, 2003, theentire contents of both of which applications are incorporated herein byreference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to an abuse-proofed, thermoformed dosageform containing, in addition to one or more active ingredients withabuse potential (A) optionally together with physiologically acceptableauxiliary substances (B), at least one synthetic or natural polymer (C)and optionally at least one wax (D), wherein component (C) exhibits abreaking strength of at least 500 N, and to a process for the productionof the dosage form according to the invention.

2. Description of Related Art

Many pharmaceutical active ingredients, in addition to having excellentactivity in their appropriate application, also have abuse potential,i.e. they can be used by an abuser to bring about effects other thanthose intended. Opiates, for example, which are highly active incombating severe to very severe pain, are frequently used by abusers toinduce a state of narcosis or euphoria.

In order to make abuse possible, the corresponding dosage forms, such astablets or capsules are comminuted, for example ground in a mortar, bythe abuser, the active ingredient is extracted from the resultant powderusing a preferably aqueous liquid and the resultant solution, optionallyafter being filtered through cotton wool or cellulose wadding, isadministered parenterally, in particular intravenously. An additionalphenomenon of this kind of administration, in comparison with abusiveoral administration, is a further accelerated increase in activeingredient levels giving the abuser the desired effect, namely the“kick” or “rush”. This kick is also obtained if the powdered dosage formis administered nasally, i.e. is sniffed. Since controlled-releasedosage forms containing active ingredients with abuse potential do notgive rise to the kick desired by the abuser when taken orally even inabusively high quantities, such dosage forms are also comminuted andextracted in order to be abused.

U.S. Pat. No. 4,070,494 proposed adding a swellable agent to the dosageform in order to prevent abuse. When water is added to extract theactive ingredient, this agent swells and ensures that the filtrateseparated from the gel contains only a small quantity of activeingredient.

The multilayer tablet disclosed in WO 95/20947 is based on a similarapproach to preventing parenteral abuse, said tablet containing theactive ingredient with abuse potential and at least one gel former, eachin different layers.

WO 03/015531 A2 discloses another approach to preventing parenteralabuse. A dosage form containing an analgesic opioid and a dye as anaversive agent is described therein. The colour released by tamperingwith the dosage form is intended to discourage the abuser from using thedosage form which has been tampered with.

Another known option for complicating abuse involves adding antagoniststo the active ingredients to the dosage form, for example naloxone ornaltexone in the case of opiates, or compounds which cause aphysiological defence response, such as for example Radixipecacuanha=ipecac root.

However, since in most cases of abuse it is still necessary to pulverisethe dosage form comprising an active ingredient suitable for abuse, itwas the object of the present invention to complicate or prevent thepulverisation preceding abuse of the dosage form comprising the agentsconventionally available for potential abuse and accordingly to providea dosage form for active ingredients with abuse potential which ensuresthe desired therapeutic effect when correctly administered, but fromwhich the active ingredients cannot be converted into a form suitablefor abuse simply by pulverisation.

SUMMARY OF THE INVENTION

Said object has been achieved by the provision of the abuse-proofed,thermoformed dosage form according to the invention which contains, inaddition to one or more active ingredients with abuse potential (A), atleast one synthetic or natural polymer (C) and optionally at least onewax (D), wherein component (C) exhibits a breaking strength of at least500 N.

DETAILED DESCRIPTION OF THE INVENTION

The use of polymers having the stated minimum breaking strength,preferably in quantities such that the dosage form also exhibits such aminimum breaking strength, means that pulverisation of the dosage formis considerably more difficult using conventional means, so considerablycomplicating or preventing the subsequent abuse.

If comminution is inadequate, parenteral, in particular intravenous,administration cannot be performed safely or extraction of the activeingredient therefrom takes too long for the abuser or there is no “kick”when taken orally, as release is not spontaneous.

According to the invention, comminution is taken to mean pulverisationof the dosage form with conventional means which are available to anabuser, such as for example a mortar and pestle, a hammer, a mallet orother usual means for pulverisation by application of force.

The dosage form according to the invention is thus suitable forpreventing parenteral, nasal and/or oral abuse of pharmaceutical activeingredients with abuse potential.

Pharmaceutical active ingredients with abuse potential are known to theperson skilled in the art, as are the quantities thereof to be used andprocesses for the production thereof, and may be present in the dosageform according to the invention as such, in the form of thecorresponding derivatives thereof, in particular esters or ethers, or ineach case in the form of corresponding physiologically acceptablecompounds, in particular in the form of the salts or solvates thereof,as racemates or stereoisomers. The dosage form according to theinvention is also suitable for the administration of several activeingredients. It is preferably used to administer a specific activeingredient.

The dosage form according to the invention is in particular suitable forpreventing abuse of a pharmaceutical active ingredient selected from thegroup consisting of opiates, opioids, tranquillisers, preferablybenzodiazepines, barbiturates, stimulants and other narcotics.

The dosage form according to the invention is very particularly suitablefor preventing abuse of an opiate, opioid, tranquilliser or anothernarcotic selected from the group consisting ofN-{1-[2-(4-ethyl-5-oxo-2-tetrazolin-1-yl)ethyl]-4-methoxymethyl-4-piperidyl}propionanilide(alfentanil), 5,5-diallylbarbituric acid (allobarbital), allylprodine,alphaprodine,8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]-benzodiazepine(alprazolam), 2-diethylaminopropiophenone (amfepramone),(±)-α-methyl-phenethylamine (amphetamine),2-(α-methylphenethylamino)-2-phenylacetonitrile (amphetaminil),5-ethyl-5-isopentylbarbituric acid (amobarbital), anileridine,apocodeine, 5,5-diethylbarbituric acid (barbital), benzylmorphine,bezitramide, 7-bromo-5-(2-pyridyl)-1H-1,4-benzodiazepine-2(3H)-one(bromazepam),2-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo-[4,3-a][1,4]diazepine(brotizolam),17-cyclopropylmethyl-4,5α-epoxy-7α[(S)-1-hydroxy-1,2,2-trimethyl-propyl]-6-methoxy-6,14-endo-ethanomorphinane-3-ol(buprenorphine), 5-butyl-5-ethylbarbituric acid (butobarbital),butorphanol,(7-chloro-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepine-3-yl)-dimethylcarbamate(camazepam), (1S,2S)-2-amino-1-phenyl-1-propanol(cathine/D-norpseudoephedrine),7-chloro-N-methyl-5-phenyl-3H-1,4-benzodiazepine-2-ylamine-4-oxide(chlorodiazepoxide),7-chloro-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione(clobazam), 5-(2-chlorophenyl)-7-nitro-1H-1,4-benzodiazepine-2(3H)-one(clonazepam), clonitazene,7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylicacid (clorazepate),5-(2-chlorophenyl)-7-ethyl-1-methyl-1H-thieno[2,3-e][1,4]diazepine-2(3H)-one(clotiazepam),10-chloro-11b-(2-chlorophenyl)-2,3,7,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepine-6(5H)-one(cloxazolam), (−)-methyl-[3β-benzoyloxy-2β(1αH,5αH)-tropancarboxylate](cocaine), 4,5α-epoxy-3-methoxy-17-methyl-7-morphinene-6α-ol (codeine),5-(1-cyclohexenyl)-5-ethylbarbituric acid (cyclobarbital), cyclorphan,cyprenorphine,7-chloro-5-(2-chlorophenyl)-1H-1,4-benzodiazepine-2(3H)-one(delorazepam), desomorphine, dextromoramide,(+)-(1-benzyl-3-dimethylamino-2-methyl-1-phenylpropyl)propionate(dextropropoxyphen), dezocine, diampromide, diamorphone,7-chloro-1-methyl-5-phenyl-1H-1,4-benzodiazepine-2(3H)-one (diazepam),4,5α-epoxy-3-methoxy-17-methyl-6α-morphinanol (dihydrocodeine),4,5α-epoxy-17-methyl-3,6α-morphinandiol (dihydromorphine), dimenoxadol,dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone,(6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-1-ol(dronabinol), eptazocine,8-chloro-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine(estazolam), ethoheptazine, ethylmethylthiambutene, ethyl[7-chloro-5-(2-fluorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-3-carboxylate](ethyl loflazepate), 4,5α-epoxy-3-ethoxy-17-methyl-7-morphinene-6α-ol(ethylmorphine), etonitazene,4,5α-epoxy-7α-(1-hydroxy-1-methylbutyl)-6-methoxy-17-methyl-6,14-endo-etheno-morphinan-3-ol(etorphine), N-ethyl-3-phenyl-8,9,10-trinorbornan-2-ylamine(fencamfamine), 7-[2-(α-methyl-phenethylamino)ethyl]-theophylline)(fenethylline), 3-(α-methylphenethylamino)propionitrile (fenproporex),N-(1-phenethyl-4-piperidyl)propionanilide (fentanyl),7-chloro-5-(2-fluorophenyl)-1-methyl-1H-1,4-benzodiazepine-2(3H)-one(fludiazepam),5-(2-fluorophenyl)-1-methyl-7-nitro-1H-1,4-benzodiazepine-2(3H)-one(flunitrazepam),7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1H-1,4-benzodiazepine-2(3H)-one(flurazepam),7-chloro-5-phenyl-1-(2,2,2-trifluoroethyl)-1H-1,4-benzodiazepine-2(3H)-one(halazepam),10-bromo-11b-(2-fluorophenyl)-2,3,7,11b-tetrahydro[1,3]oxazolyl[3,2-d][1,4]benzodiazepine-6(5H)-one(haloxazolam), heroin, 4,5α-epoxy-3-methoxy-17-methyl-6-morphinanone(hydrocodone), 4,5α-epoxy-3-hydroxy-17-methyl-6-morphinanone(hydromorphone), hydroxypethidine, isomethadone, hydroxymethylmorphinane,11-chloro-8,12b-dihydro-2,8-dimethyl-12b-phenyl-4H-[1,3]oxazino[3,2-d][1,4]benzodiazepine-4,7(6H)-dione(ketazolam), 1-[4-(3-hydroxyphenyl)-1-methyl-4-piperidyl]-1-propanone(ketobemidone), (3S,6S)-6-dimethylamino-4,4-diphenylheptan-3-yl acetate(levacetylmethadol (LAAM)), (−)-6-dimethylamino-4,4-diphenol-3-heptanone(levomethadone), (−)-17-methyl-3-morphinanol (levorphanol),levophenacylmorphane, lofentanil,6-(2-chlorophenyl)-2-(4-methyl-1-piperazinylmethylene)-8-nitro-2H-imidazo[1,2-a][1,4]-benzodiazepine-1(4H)-one(loprazolam),7-chloro-5-(2-chlorophenyl)-3-hydroxy-1H-1,4-benzodiazepine-2(3H)-one(lorazepam),7-chloro-5-(2-chlorophenyl)-3-hydroxy-1-methyl-1H-1,4-benzodiazepine-2(3H)-one(lormetazepam),5-(4-chlorophenyl)-2,5-dihydro-3H-imidazo[2,1-a]isoindol-5-ol(mazindol), 7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine(medazepam), N-(3-chloropropyl)-α-methylphenethylamine (mefenorex),meperidine, 2-methyl-2-propyltrimethylene dicarbamate (meprobamate),meptazinol, metazocine, methylmorphine, N,α-dimethylphenethylamine(methamphetamine), (±)-6-dimethylamino-4,4-diphenyl-3-heptanone(methadone), 2-methyl-3-o-tolyl-4(3H)-quinazolinone (methaqualone),methyl [2-phenyl-2-(2-piperidyl)acetate] (methylphenidate),5-ethyl-1-methyl-5-phenylbarbituric acid (methylphenobarbital),3,3-diethyl-5-methyl-2,4-piperidinedione (methyprylon), metopon,8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine(midazolam), 2-(benzhydrylsulfinyl)-acetamide (modafinil),4,5α-epoxy-17-methyl-7-morphinen-3,6α-diol (morphine), myrophine,(±)-trans-3-(1,1-dimethylheptyl)-7,8,10,10α-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo[b,d]pyrane-9(6αH)-one(nabilone), nalbuphine, nalorphine, narceine, nicomorphine,1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepine-2(3H)-one (nimetazepam),7-nitro-5-phenyl-1H-1,4-benzodiazepine-2(3H)-one (nitrazepam),7-chloro-5-phenyl-1H-1,4-benzodiazepine-2(3H)-one (nordazepam),norlevorphanol, 6-dimethylamino-4,4-diphenyl-3-hexanone (normethadone),normorphine, norpipanone, the exudation of plants belonging to thespecies Papaver somniferum (opium),7-chloro-3-hydroxy-5-phenyl-1H-1,4-benzodiazepine-2(3H)-one (oxazepam),(cis-trans)-10-chloro-2,3,7,11b-tetrahydro-2-methyl-11b-phenyloxazolo[3,2-d][1,4]benzodiazepine-6-(5H)-one(oxazolam), 4,5α-epoxy-14-hydroxy-3-methoxy-17-methyl-6-morphinanone(oxycodone), oxymorphone, plants and parts of plants belonging to thespecies Papaver somniferum (including the subspecies setigerum),papavereturn, 2-imino-5-phenyl-4-oxazolidinone (pernoline),1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2,6-methano-3-benzazocin-8-ol(pentazocine), 5-ethyl-5-(1-methylbutyl)-barbituric acid(pentobarbital), ethyl-(1-methyl-4-phenyl-4-piperidine carboxylate)(pethidine), phenadoxone, phenomorphan, phenazocine, phenoperidine,piminodine, pholcodine, 3-methyl-2-phenylmorpholine (phenmetrazine),5-ethyl-5-phenylbarbituric acid (phenobarbital),α,α-dimethylphenethylamine (phentermine),7-chloro-5-phenyl-1-(2-propynyl)-1H-1,4-benzodiazepine-2(3H)-one(pinazepam), α-(2-piperidyl)benzhydryl alcohol (pipradrol),1′-(3-cyano-3,3-diphenylpropyl)[1,4′-bipiperidine]-4′-carboxamide(piritramide),7-chloro-1-(cyclopropylmethyl)-5-phenyl-1H-1,4-benzodiazepine-2(3H)-one(prazepam), profadol, proheptazine, promedol, properidine, propoxyphene,N-(1-methyl-2-piperidinoethyl)-N-(2-pyridyl)propionamide, methyl{3-[4-methoxycarbonyl-4-(N-phenylpropanamido)piperidino]propanoate}(remifentanil), 5-sec-butyl-5-ethylbarbituric acid (secbutabarbital),5-allyl-5-(1-methylbutyl)-barbituric acid (secobarbital),N-{4-methoxymethyl-1-[2-(2-thienyl)ethyl]-4-piperidyl}-propionanilide(sufentanil),7-chloro-2-hydroxy-methyl-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one(temazepam),7-chloro-5-(1-cyclohexenyl)-1-methyl-1H-1,4-benzodiazepine-2(3H)-one(tetrazepam), ethyl(2-dimethylamino-1-phenyl-3-cyclohexene-1-carboxylate) (tilidine (cisand trans)), tramadol,8-chloro-6-(2-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine(triazolam), 5-(1-methylbutyl)-5-vinylbarbituric acid (vinylbital),(1R*,2R*)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,(1R,2R,4S)-2-(dimethylamino)methyl-4-(p-fluoro-benzyloxy)-1-(m-methoxyphenyl)cyclohexanol,(1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)phenol,(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol,(2R,3R)-1-dimethylamino-3(3-methoxyphenyl)-2-methyl-pentan-3-ol,(1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol,3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl2-(4-isobutoxy-phenyl)-propionate,3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl2-(6-methoxy-naphthalen-2-yl)-propionate,3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl2-(4-isobutyl-phenyl)-propionate,3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl2-(6-methoxy-naphthalen-2-yl)-propionate,(RR-SS)-2-acetoxy-4-trifluoromethyl-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR-SS)-2-hydroxy-4-trifluoromethyl-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR-SS)-4-chloro-2-hydroxy-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR-SS)-2-hydroxy-4-methyl-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR-SS)-2-hydroxy-4-methoxy-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR-SS)-2-hydroxy-5-nitro-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR-SS)-2′,4′-difluoro-3-hydroxy-biphenyl-4-carboxylic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester and forcorresponding stereoisomeric compounds, the corresponding derivativesthereof in each case, in particular esters or ethers, and thephysiologically acceptable compounds thereof in each case, in particularthe salts and solvates thereof.

The compounds(1R*,2R*)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,(1R,2R,4S)-2-(dimethylamino)methyl-4-(p-fluorobenzyloxy)-1-(m-methoxyphenyl)cyclohexanolor the stereoisomeric compounds thereof or the physiologicallyacceptable compounds thereof, in particular the hydrochlorides thereof,the derivatives thereof, such as esters or ethers, and processes for theproduction thereof are known, for example, from EP-A-693475 orEP-A-780369. The corresponding descriptions are hereby introduced as areference and are deemed to be part of the disclosure.

In order to achieve the necessary breaking strength of the dosage formaccording to the invention, at least one synthetic or natural polymer(C) is used which has a breaking strength, measured using the methoddisclosed in the present application, of at least 500 N. At least onepolymer selected from the group consisting of polymethylene oxide,polyethylene oxide, polypropylene oxide, polyethylene, polypropylene,polyvinyl chloride, polycarbonate, polystyrene, polyacrylate, copolymersthereof, and mixtures of at least two of the stated polymers ispreferably used for this purpose. The polymers are distinguished by amolecular weight of at least 0.5 million, determined by rheologicalmeasurements. Thermoplastic polyalkylene oxides, such as polyethyleneoxides, with a molecular weight of at least 0.5 million, preferably ofup to 15 million, determined by rheological measurements, are veryparticularly preferred. These polymers have a viscosity at 25° C. of4500 to 17600 cP, measured on a 5 wt. % aqueous solution using a modelRVF Brookfield viscosimeter (spindle no. 2/rotational speed 2 rpm), of400 to 4000 cP, measured on a 2 wt. % aqueous solution using the statedviscosimeter (spindle no. 1 or 3/rotational speed 10 rpm) or of 1650 to10000 cP, measured on a 1 wt. % aqueous solution using the statedviscosimeter (spindle no. 2/rotational speed 2 rpm).

The polymers are used in powder form.

In order to achieve the necessary breaking strength of the dosage formaccording to the invention, it is furthermore possible additionally touse at least one natural or synthetic wax (D) with a breaking strength,measured using the method disclosed in the present application, of atleast 500 N. Waxes with a softening point of at least 60° C. arepreferred. Carnauba wax and beeswax are particularly preferred. Carnaubawax is very particularly preferred.

Carnauba wax is a natural wax which is obtained from the leaves of thecarnauba palm and has a softening point of 80° C. When the wax componentis additionally used, it is used together with at least one polymer (C)in quantities such that the dosage form has a breaking strength of atleast 500 N.

The dosage forms according to the invention are distinguished in that,due their hardness, they cannot be pulverised, for example by grindingin a mortar. This virtually rules out oral or parenteral, in particularintravenous or nasal abuse. However, in order to prevent any possibleabuse in the event of comminution and/or pulverisation of the dosageform according to the invention which has nevertheless been achieved byapplication of extreme force, the dosage forms according to theinvention may, in a preferred embodiment, contain further agents whichcomplicate or prevent abuse as auxiliary substances (B).

The abuse-proofed dosage form according to the invention, whichcomprises, apart from one or more active ingredients with abusepotential, at least one hardening polymer (C) and optionally at leastone wax (D), may accordingly also comprise at least one of the followingcomponents (a)-(f) as auxiliary substances (B):

-   (a) at least one substance which irritates the nasal passages and/or    pharynx,-   (b) at least one viscosity-increasing agent, which, with the    assistance of a necessary minimum quantity of an aqueous liquid,    forms a gel with the extract obtained from the dosage form, which    gel preferably remains visually distinguishable when introduced into    a further quantity of an aqueous liquid,-   (c) at least one antagonist for each of the active ingredients with    abuse potential,-   (d) at least one emetic,-   (e) at least one dye as an aversive agent,-   (f) at least one bitter substance.

Components (a) to (f) are additionally each individually suitable forabuse-proofing the dosage form according to the invention. Accordingly,component (a) is preferably suitable for proofing the dosage formagainst nasal, oral and/or parenteral, preferably intravenous, abuse,component (b) is preferably suitable for proofing against parenteral,particularly preferably intravenous and/or nasal abuse, component (c) ispreferably suitable for proofing against nasal and/or parenteral,particularly preferably intravenous, abuse, component (d) is preferablysuitable for proofing against parenteral, particularly preferablyintravenous, and/or oral and/or nasal abuse, component (e) is suitableas a visual deterrent against oral or parenteral abuse and component (f)is suitable for proofing against oral or nasal abuse. Combined useaccording to the invention of at least one of the above-statedcomponents makes it possible still more effectively to prevent abuse ofdosage forms according to the invention.

In one embodiment, the dosage form according to the invention may alsocomprise two or more of components (a)-(f) in a combination, preferably(a), (b) and optionally (c) and/or (f) and/or (e) or (a), (b) andoptionally (d) and/or (f) and/or (e).

In another embodiment, the dosage form according to the invention maycomprise all of components (a)-(f).

If the dosage form according to the invention comprises component (a) tocounter abuse, substances which irritate the nasal passages and/orpharynx which may be considered according to the invention are anysubstances which, when administered via the nasal passages and/orpharynx, bring about a physical reaction which is either so unpleasantfor the abuser that he/she does not wish to or cannot continueadministration, for example burning, or physiologically counteractstaking of the corresponding active ingredient, for example due toincreased nasal secretion or sneezing. These substances whichconventionally irritate the nasal passages and/or pharynx may also bringabout a very unpleasant sensation or even unbearable pain whenadministered parenterally, in particular intravenously, such that theabuser does not wish to or cannot continue taking the substance.

Particularly suitable substances which irritate the nasal passagesand/or pharynx are those which cause burning, itching, an urge tosneeze, increased formation of secretions or a combination of at leasttwo of these stimuli. Appropriate substances and the quantities thereofwhich are conventionally to be used are known per se to the skilledperson or may be identified by simple preliminary testing.

The substance which irritates the nasal passages and/or pharynx ofcomponent (a) is preferably based on one or more constituents or one ormore plant parts of at least one hot substance drug.

Corresponding hot substance drugs are known per se to the person skilledin the art and are described, for example, in “PharmazeutischeBiologie—Drogen and ihre Inhaltsstoffe” by Prof. Dr. Hildebert Wagner,2nd., revised edition, Gustav Fischer Verlag, Stuttgart-N.Y., 1982,pages 82 et seq. The corresponding description is hereby introduced as areference and is deemed to be part of the disclosure.

The dosage form according to the invention may preferably contain theplant parts of the corresponding hot substance drugs in a quantity of0.01 to 30 wt. %, particularly preferably of 0.1 to 0.5 wt. %, in eachcase relative to the total weight dosage unit.

If one or more constituents of corresponding hot substance drugs areused, the quantity thereof in a dosage unit according to the inventionpreferably amounts to 0.001 to 0.005 wt. %, relative to the total weightof the dosage unit.

A dosage unit is taken to mean a separate or separable administrationunit, such as for example a tablet or a capsule.

One or more constituents of at least one hot substance drug selectedfrom the group consisting of Allii sativi bulbus (garlic), Asari rhizomacum herba (Asarum root and leaves), Calami rhizoma (calamus root),Capsici fructus (capsicum), Capsici fructus acer (cayenne pepper),Curcumae longae rhizoma (turmeric root), Curcumae xanthorrhizae rhizoma(Javanese turmeric root), Galangae rhizoma (galangal root), Myristicaesemen (nutmeg), Piperis nigri fructus (pepper), Sinapis albae semen(white mustard seed), Sinapis nigri semen (black mustard seed),Zedoariae rhizoma (zedoary root) and Zingiberis rhizoma (ginger root),particularly preferably from the group consisting of Capsici fructus(capsicum), Capsici fructus acer (cayenne pepper) and Piperis nigrifructus (pepper) may preferably be added as component (a) to the dosageform according to the invention.

The constituents of the hot substance drugs preferably compriseo-methoxy(methyl)phenol compounds, acid amide compounds, mustard oils orsulfide compounds or compounds derived therefrom.

Particularly preferably, at least one constituent of the hot substancedrugs is selected from the group consisting of myristicin, elemicin,isoeugenol, β-asarone, safrole, gingerols, xanthorrhizol, capsaicinoids,preferably capsaicin, capsaicin derivatives, such asN-vanillyl-9E-octadecenamide, dihydrocapsaicin, nordihydrocapsaicin,homocapsaicin, norcapsaicin and nomorcapsaicin, piperine, preferablytrans-piperine, glucosinolates, preferably based on non-volatile mustardoils, particularly preferably based on p-hydroxybenzyl mustard oil,methylmercapto mustard oil or methylsulfonyl mustard oil, and compoundsderived from these constituents.

Another option for preventing abuse of the dosage form according to theinvention consists in adding at least one viscosity-increasing agent asa further abuse-preventing component (b) to the dosage form, which, withthe assistance of a necessary minimum quantity of an aqueous liquid,forms a gel with the extract obtained from the dosage form, which gel isvirtually impossible to administer safely and preferably remainsvisually distinguishable when introduced into a further quantity of anaqueous liquid.

For the purposes of the present invention visually distinguishable meansthat the active ingredient-containing gel formed with the assistance ofa necessary minimum quantity of aqueous liquid, when introduced,preferably with the assistance of a hypodermic needle, into a furtherquantity of aqueous liquid at 37° C., remains substantially insolubleand cohesive and cannot straightforwardly be dispersed in such a mannerthat it can safely be administered parenterally, in particularintravenously. The material preferably remains visually distinguishablefor at least one minute, preferably for at least 10 minutes.

The increased viscosity of the extract makes it more difficult or evenimpossible for it to be passed through a needle or injected. If the gelremains visually distinguishable, this means that the gel obtained onintroduction into a further quantity of aqueous liquid, for example byinjection into blood, initially remains in the form of a largelycohesive thread, which, while it may indeed be broken up into smallerfragments, cannot be dispersed or even dissolved in such a manner thatit can safely be administered parenterally, in particular intravenously.In combination with at least one optionally present component (a) to(e), this additionally leads to unpleasant burning, vomiting, badflavour and/or visual deterrence.

Intravenous administration of such a gel would most probably result inobstruction of blood vessels, associated with serious embolism or evendeath of the abuser.

In order to verify whether a viscosity-increasing agent is suitable ascomponent (b) for use in the dosage form according to the invention, theactive ingredient is mixed with the viscosity-increasing agent andsuspended in 10 ml of water at a temperature of 25° C. If this resultsin the formation of a gel which fulfils the above-stated conditions, thecorresponding viscosity-increasing agent is suitable for preventing oraverting abuse of the dosage forms according to the invention.

If component (b) is added to the dosage form according to the invention,one or more viscosity-increasing agents are used which are selected fromthe group consisting of microcrystalline cellulose with 11 wt. %carboxymethylcellulose sodium (Avicel® RC 591), carboxymethylcellulosesodium (Blanose®, CMC-Na C300P®, Frimulsion BLC-5®, Tylose C300 P®),polyacrylic acid (Carbopol® 980 NF, Carbopol® 981), locust bean flour(Cesagum® LA-200, Cesagum® LID/150, Cesagum® LN-1), pectins such ascitrus pectin (Cesapectin® HM Medium Rapid Set), apple pectin, pectinfrom lemon peel, waxy maize starch (C*Gel 04201®), sodium alginate(Frimulsion ALG (E401)®), guar flour (Frimulsion BM®, Polygum 26/1-75®),iota carrageen (Frimulsion D021®), karaya gum, gellan gum (Kelcogel F®,Kelcogel LT100®), galactomannan (Meyprogat 150®), tara bean flour(Polygum 43/10), propylene glycol alginate (Protanal-Ester SD-LB®),sodium hyaluronate, tragacanth, tara gum (Vidogum SP 200®), fermentedpolysaccharide welan gum (K1A96), xanthan gum (Xantural 1800). Xanthansare particularly preferred. The names stated in brackets are the tradenames by which the materials are known commercially. In general, aquantity of 0.1 to 5 wt. % of the viscosity-increasing agent(s) issufficient to fulfil the above-stated conditions.

The component (b) viscosity-increasing agents, where provided, arepreferably present in the dosage form according to the invention inquantities of ≧5 mg per dosage unit, i.e. per administration unit.

In a particularly preferred embodiment of the present invention, theviscosity-increasing agents used as component (b) are those which, onextraction from the dosage form with the necessary minimum quantity ofaqueous liquid, form a gel which encloses air bubbles. The resultantgels are distinguished by a turbid appearance, which provides thepotential abuser with an additional optical warning and discourageshim/her from administering the gel parenterally.

It is also possible to formulate the viscosity-increasing agent and theother constituents in the dosage form according to the invention in amutually spatially separated arrangement.

In order to discourage and prevent abuse, the dosage form according tothe invention may furthermore comprise component (c), namely one or moreantagonists for the active ingredient or active ingredients with abusepotential, wherein the antagonists are preferably spatially separatedfrom the remaining constituents of the invention dosage according to theform and, when correctly used, do not exert any effect.

Suitable antagonists for preventing abuse of the active ingredients areknown per se to the person skilled in the art and may be present in thedosage form according to the invention as such or in the form ofcorresponding derivatives, in particular esters or ethers, or in eachcase in the form of corresponding physiologically acceptable compounds,in particular in the form of the salts or solvates thereof.

If the active ingredient present in the dosage form is an opiate or anopioid, the antagonist used is preferably an antagonist selected fromthe group consisting of naloxone, naltrexone, nalmefene, nalid,nalmexone, nalorphine or naluphine, in each case optionally in the formof a corresponding physiologically acceptable compound, in particular inthe form of a base, a salt or solvate. The corresponding antagonists,where component (c) is provided, are preferably used in a quantity of≧10 mg, particularly preferably in a quantity of 10 to 100 mg, veryparticularly preferably in a quantity of 10 to 50 mg per dosage form,i.e. per administration unit.

If the dosage form according to the invention comprises a stimulant asactive ingredient, the antagonist is preferably a neuroleptic,preferably at least one compound selected from the group consisting ofhaloperidol, promethazine, fluphenazine, perphenazine, levomepromazine,thioridazine, perazine, chlorpromazine, chlorprothixine, zuclopentixol,flupentixol, prothipendyl, zotepine, benperidol, pipamperone, melperoneand bromperidol.

The dosage form according to the invention preferably comprises theseantagonists in a conventional therapeutic dose known to the personskilled in the art, particularly preferably in a quantity of twice tofour times the conventional dose per administration unit.

If the combination to discourage and prevent abuse of the dosage formaccording to the invention comprises component (d), it may comprise atleast one emetic, which is preferably present in a spatially separatedarrangement from the other components of the dosage form according tothe invention and, when correctly used, is intended not to exert itseffect in the body.

Suitable emetics for preventing abuse of an active ingredient are knownper se to the person skilled in the art and may be present in the dosageform according to the invention as such or in the form of correspondingderivatives, in particular esters or ethers, or in each case in the formof corresponding physiologically acceptable compounds, in particular inthe form of the salts or solvates thereof.

An emetic based on one or more constituents of radix ipecacuanha (ipecacroot), preferably based on the constituent emetine may preferably beconsidered in the dosage form according to the invention, as are, forexample, described in “Pharmazeutische Biologie—Drogen and ihreInhaltsstoffe” by Prof. Dr. Hildebert Wagner, 2nd, revised edition,Gustav Fischer Verlag, Stuttgart, N.Y., 1982. The correspondingliterature description is hereby introduced as a reference and is deemedto be part of the disclosure.

The dosage form according to the invention may preferably comprise theemetic emetine as component (d), preferably in a quantity of 10 mg,particularly preferably of 20 mg and very particularly preferably in aquantity of 40 mg per dosage form, i.e. administration unit.

Apomorphine may likewise preferably be used as an emetic in theabuse-proofing according to the invention, preferably in a quantity ofpreferably 3 mg, particularly preferably of 5 mg and very particularlypreferably of 7 mg per administration unit.

If the dosage form according to the invention contains component (e) asa further abuse-preventing auxiliary substance, the use of a such a dyebrings about an intense coloration of a corresponding aqueous solution,in particular when the attempt is made to extract the active ingredientfor parenteral, preferably intravenous administration, which colorationmay act as a deterrent to the potential abuser. Oral abuse, whichconventionally begins by means of aqueous extraction of the activeingredient, may also be prevented by this coloration. Suitable dyes andthe quantities required for the necessary deterrence may be found in WO03/015531, wherein the corresponding disclosure should be deemed to bepart of the present disclosure and is hereby introduced as a reference.

If the dosage form according to the invention contains component (f) asa further abuse-preventing auxiliary substance, this addition of atleast one bitter substance and the consequent impairment of the flavourof the dosage form additionally prevents oral and/or nasal abuse.

Suitable bitter substances and the quantities effective for use may befound in US-2003/0064099 A1, the corresponding disclosure of whichshould be deemed to be the disclosure of the present application and ishereby introduced as a reference. Suitable bitter substances arepreferably aromatic oils, preferably peppermint oil, eucalyptus oil,bitter almond oil, menthol, fruit aroma substances, preferably aromasubstances from lemons, oranges, limes, grapefruit or mixtures thereof,and/or denatonium benzoate.

The solid dosage form according to the invention is suitable to be takenorally or rectally, preferably orally.

The orally administrable dosage form according to the invention mayassume multiparticulate form, preferably in the form of microtablets,microcapsules, micropellets, granules, spheroids, beads or pellets,optionally packaged in capsules or pressed into tablets. Themultiparticulate forms preferably have a size or size distribution inthe range from 0.1 to 3 mm, particularly preferably in the range from0.5 to 2 mm. Depending on the desired dosage form, conventionalauxiliary substances (B) are optionally also used for the formulation ofthe dosage form.

The solid, abuse-proofed dosage form according to the invention ispreferably produced by mixing the components (A), (B), (C)and/optionally (D) and at least one of the optionally present furtherabuse-preventing components (a)-(f) and, optionally after granulation,press-forming the resultant mixture to yield the dosage form withpreceding, simultaneous, or subsequent exposure to heat.

Mixing of components (A), (B), (C) and optionally (D) and of theoptionally present further components (a)-(f) proceeds in a mixer knownto the person skilled in the art. The mixer may, for example, be a rollmixer, shaking mixer, shear mixer or compulsory mixer.

The resultant mixture is preferably formed directly by application ofpressure to yield the dosage form according to the invention withpreceding, simultaneous or subsequent exposure to heat. The mixture may,for example, be formed into tablets by direct tabletting. In directtabletting with simultaneous exposure to heat, the tabletting tool, i.e.bottom punch, top punch and die are briefly heated at least to thesoftening temperature of the polymer (C) and pressed together. In directtabletting with subsequent exposure to heat, the formed tablets arebriefly heated at least to the softening temperature (glass transitiontemperature, melting temperature; sintering temperature) of component(C) and cooled again. In direct tabletting with preceding exposure toheat, the material to be pressed is heated immediately prior totabletting at least to the softening temperature of component (C) andthen pressed.

The resultant mixture of components (A), (B), (C) and optionally (D) andthe optionally present components (a) to (f) may also first begranulated and then be formed with preceding, simultaneous, orsubsequent exposure to heat to yield the dosage form according to theinvention.

In a further preferred embodiment, the dosage form according to theinvention assumes the form of a tablet, a capsule or is in the form ofan oral osmotic therapeutic system (OROS), preferably if at least onefurther abuse-preventing component (a)-(f) is also present.

If components (c) and/or (d) and/or (f) are present in the dosage formaccording to the invention, care must be taken to ensure that they areformulated in such a manner or are present in such a low dose that, whencorrectly administered, the dosage form is able to bring about virtuallyno effect which impairs the patient or the efficacy of the activeingredient.

If the dosage form according to the invention contains component (d)and/or (f), the dosage must be selected such that, when correctly orallyadministered, no negative effect is caused. If, however, the intendeddosage of the dosage form is exceeded inadvertently, in particular bychildren, or in the event of abuse, nausea or an inclination to vomit ora bad flavour are produced. The particular quantity of component (d)and/or (f) which can still be tolerated by the patient in the event ofcorrect oral administration may be determined by the person skilled inthe art by simple preliminary testing.

If, however, irrespective of the fact that the dosage form according tothe invention is virtually impossible to pulverise, the dosage formcontaining the components (c) and/or (d) and/or (f) is provided withprotection, these components should preferably be used at a dosage whichis sufficiently high that, when abusively administered, they bring aboutan intense negative effect on the abuser. This is preferably achieved byspatial separation of at least the active ingredient or activeingredients from components (c) and/or (d) and/or (f), wherein theactive ingredient or active ingredients is/are present in at least onesubunit (X) and components (c) and/or (d) and/or (f) is/are present inat least one subunit (Y), and wherein, when the dosage form is correctlyadministered, components (c), (d) and (f) do not exert their effect ontaking and/or in the body and the remaining components of theformulation, in particular component (C), are identical.

If the dosage form according to the invention comprises at least 2 ofcomponents (c) and (d) or (f), these may each be present in the same ordifferent subunits (Y). Preferably, when present, all the components (c)and (d) and (f) are present in one and the same subunit (Y).

For the purposes of the present invention, subunits are solidformulations, which in each case, apart from conventional auxiliarysubstances known to the person skilled in the art, contain the activeingredient(s), at least one polymer (C) and optionally at least one ofthe optionally present components (a) and/or (b) and/or (e) or in eachcase at least one polymer (C) and the antagonist(s) and/or emetic(s)and/or component (e) and/or component (f) and optionally at least one ofthe optionally present components (a) and/or (b). Care must here betaken to ensure that each of the subunits is formulated in accordancewith the above-stated process.

One substantial advantage of the separated formulation of activeingredients from components (c) or (d) or (f) in subunits (X) and (Y) ofthe dosage form according to the invention is that, when correctlyadministered, components (c) and/or (d) and/or (f) are hardly releasedon taking and/or in the body or are released in such small quantitiesthat they exert no effect which impairs the patient or therapeuticsuccess or, on passing through the patient's body, they are onlyliberated in locations where they cannot be sufficiently absorbed to beeffective. When the dosage form is correctly administered, hardly any ofcomponents (c) and/or (d) and/or (f) is released into the patient's bodyor they go unnoticed by the patient.

The person skilled in the art will understand that the above-statedconditions may vary as a function of the particular components (c), (d)and/or (f) used and of the formulation of the subunits or the dosageform. The optimum formulation for the particular dosage form may bedetermined by simple preliminary testing. What is vital is that eachsubunit contains the polymer (C) and has been formulated in the statedmanner.

Should, contrary to expectations, the abuser succeed in comminuting sucha dosage form according to the invention, which comprises components (c)and/or (e) and/or (d) and/or (f) in subunits (Y), for the purpose ofabusing the active ingredient and obtain a powder which is extractedwith a suitable extracting agent, not only the active ingredient butalso the particular component (c) and/or (e) and/or (f) and/or (d) willbe obtained in a form in which it cannot readily be separated from theactive ingredient, such that when the dosage form which has beentampered with is administered, in particular by oral and/or parenteraladministration, it will exert its effect on taking and/or in the bodycombined with an additional negative effect on the abuser correspondingto component (c) and/or (d) and/or (f) or, when the attempt is made toextract the active ingredient, the coloration will act as a deterrentand so prevent abuse of the dosage form.

A dosage form according to the invention, in which the active ingredientor active ingredients is/are spatially separated from components (c),(d) and/or (e), preferably by formulation in different subunits, may beformulated in many different ways, wherein the corresponding subunitsmay each be present in the dosage form according to the invention in anydesired spatial arrangement relative to one another, provided that theabove-stated conditions for the release of components (c) and/or (d) arefulfilled.

The person skilled in the art will understand that component(s) (a)and/or (b) which are optionally also present may preferably beformulated in the dosage form according to the invention both in theparticular subunits (X) and (Y) and in the form of independent subunitscorresponding to subunits (X) and (Y), provided that neither theabuse-proofing nor the active ingredient release in the event of correctadministration is impaired by the nature of the formulation and thepolymer (C) is included in the formulation and formulation is carriedout in accordance with the above-stated process.

In a preferred embodiment of the dosage form according to the invention,subunits (X) and (Y) are present in multiparticulate form, whereinmicrotablets, microcapsules, micropellets, granules, spheroids, beads orpellets are preferred and the same form, i.e. shape, is selected forboth subunit (X) and subunit (Y), such that it is not possible toseparate subunits (X) from (Y) by mechanical selection. Themultiparticulate forms are preferably of a size in the range from 0.1 to3 mm, preferably of 0.5 to 2 mm.

The subunits (X) and (Y) in multiparticulate form may also preferably bepackaged in a capsule or be pressed into a tablet, wherein the finalformulation in each case proceeds in such a manner that the subunits (X)and (Y) are also retained in the resultant dosage form.

The multiparticulate subunits (X) and (Y) of identical shape should alsonot be visually distinguishable from one another so that the abusercannot separate them from one another by simple sorting. This may, forexample, be achieved by the application of identical coatings which,apart from this disguising function, may also incorporate furtherfunctions, such as, for example, controlled release of one or moreactive ingredients or provision of a finish resistant to gastric juiceson the particular subunits.

In a further preferred embodiment of the present invention, subunits (X)and (Y) are in each case arranged in layers relative to one another.

The layered subunits (X) and (Y) are preferably arranged for thispurpose vertically or horizontally relative to one another in the dosageform according to the invention, wherein in each case one or morelayered subunits (X) and one or more layered subunits (Y) may be presentin the dosage form, such that, apart from the preferred layer sequences(X)-(Y) or (X)-(Y)-(X), any desired other layer sequences may beconsidered, optionally in combination with layers containing components(a) and/or (b).

Another preferred dosage form according to the invention is one in whichsubunit (Y) forms a core which is completely enclosed by subunit (X),wherein a separation layer (Z) may be present between said layers. Sucha structure is preferably also suitable for the above-statedmultiparticulate forms, wherein both subunits (X) and (Y) and anoptionally present separation layer (Z), which must satisfy the hardnessrequirement according to the invention, are formulated in one and thesame multiparticulate form. In a further preferred embodiment of thedosage form according to the invention, the subunit (X) forms a core,which is enclosed by subunit (Y), wherein the latter comprises at leastone channel which leads from the core to the surface of the dosage form.

The dosage form according to the invention may comprise, between onelayer of the subunit (X) and one layer of the subunit (Y), in each caseone or more, preferably one, optionally swellable separation layer (Z)which serves to separate subunit (X) spatially from (Y).

If the dosage form according to the invention comprises the layeredsubunits (X) and (Y) and an optionally present separation layer (Z) inan at least partially vertical or horizontal arrangement, the dosageform preferably takes the form of a tablet, a coextrudate or a laminate.

In one particularly preferred embodiment, the entirety of the freesurface of subunit (Y) and optionally at least part of the free surfaceof subunit(s) (X) and optionally at least part of the free surface ofthe optionally present separation layer(s) (Z) may be coated with atleast one barrier layer (Z′) which prevents release of component (c)and/or (e) and/or (d) and/or (f). The barrier layer (Z′) must alsofulfil the hardness conditions according to the invention.

Another particularly preferred embodiment of the dosage form accordingto the invention comprises a vertical or horizontal arrangement of thelayers of subunits (X) and (Y) and at least one push layer (p) arrangedtherebetween, and optionally a separation layer (Z), in which dosageform the entirety of the free surface of layer structure consisting ofsubunits (X) and (Y), the push layer and the optionally presentseparation layer (Z) is provided with a semipermeable coating (E), whichis permeable to a release medium, i.e. conventionally a physiologicalliquid, but substantially impermeable to the active ingredient and tocomponent (c) and/or (d) and/or (f), and wherein this coating (E)comprises at least one opening for release of the active ingredient inthe area of subunit (X).

A corresponding dosage form is known to the person skilled in the art,for example under the name oral osmotic therapeutic system (OROS), asare suitable materials and methods for the production thereof, interalia from U.S. Pat. No. 4,612,008, U.S. Pat. No. 4,765,989 and U.S. Pat.No. 4,783,337. The corresponding descriptions are hereby introduced as areference and are deemed to be part of the disclosure.

In a further preferred embodiment, the subunit (X) of the dosage formaccording to the invention is in the form of a tablet, the edge face ofwhich and optionally one of the two main faces is covered with a barrierlayer (Z′) containing component (c) and/or (d) and/or (f).

The person skilled in the art will understand that the auxiliarysubstances of the subunit(s) (X) or (Y) and of the optionally presentseparation layer(s) (Z) and/or of the barrier layer(s) (Z′) used informulating the dosage form according to the invention will vary as afunction of the arrangement thereof in the dosage form according to theinvention, the mode of administration and as a function of theparticular active ingredient of the optionally present components (a)and/or (b) and/or (e) and of component (c) and/or (d) and/or (f). Thematerials which have the requisite properties are in each case known perse to the person skilled in the art.

If release of component (c) and/or (d) and/or (f) from subunit (Y) ofthe dosage form according to the invention is prevented with theassistance of a cover, preferably a barrier layer, the subunit mayconsist of conventional materials known to the person skilled in theart, providing that it contains at least one polymer (C) to fulfil thehardness condition of the dosage form according to the invention.

If a corresponding barrier layer (Z′) is not provided to prevent releaseof component (c) and/or (d) and/or (f), the materials of the subunitsshould be selected such that release of the particular component (c)and/or (d) from subunit (Y) is virtually ruled out. The materials whichare stated below to be suitable for production of the barrier layer maypreferably be used for this purpose. The materials for the separationlayer and/or barrier layer must contain at least one polymer (C) inorder to fulfil the hardness conditions.

Preferred materials are those which are selected from the groupconsisting of alkylcelluloses, hydroxyalkylcelluloses, glucans,scleroglucans, mannans, xanthans, copolymers ofpoly[bis(p-carboxyphenoxy)propane and sebacic acid, preferably in amolar ratio of 20:80 (commercially available under the name Polifeprosan20®), carboxymethylcelluloses, cellulose ethers, cellulose esters,nitrocelluloses, polymers based on (meth)acrylic acid and the estersthereof, polyamides, polycarbonates, polyalkylenes, polyalkyleneglycols, polyalkylene oxides, polyalkylene terephthalates, polyvinylalcohols, polyvinyl ethers, polyvinyl esters, halogenated polyvinyls,polyglycolides, polysiloxanes and polyurethanes and the copolymersthereof.

Particularly suitable materials may be selected from the groupconsisting of methylcellulose, ethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, hydroxybutylmethylcellulose, celluloseacetate, cellulose propionate (of low, medium or high molecular weight),cellulose acetate propionate, cellulose acetate butyrate, celluloseacetate phthalate, carboxymethylcellulose, cellulose triacetate, sodiumcellulose sulfate, polymethyl methacrylate, polyethyl methacrylate,polybutyl methacrylate, polyisobutyl methacrylate, polyhexylmethacrylate, polyisodecyl methacrylate, polylauryl methacrylate,polyphenyl methacrylate, polymethyl acrylate, polyisopropyl acrylate,polyisobutyl acrylate, polyoctadecyl acrylate, polyethylene, low densitypolyethylene, high density polyethylene, polypropylene, polyethyleneglycol, polyethylene oxide, polyethylene terephthalate, polyvinylalcohol, polyvinyl isobutyl ether, polyvinyl acetate and polyvinylchloride.

Particularly suitable copolymers may be selected from the groupconsisting of copolymers of butyl methacrylate and isobutylmethacrylate, copolymers of methyl vinyl ether and maleic acid with highmolecular weight, copolymers of methyl vinyl ether and maleic acidmonoethyl ester, copolymers of methyl vinyl ether and maleic anhydrideand copolymers of vinyl alcohol and vinyl acetate.

Further materials which are particularly suitable for formulating thebarrier layer are starch-filled polycaprolactone (WO98/20073), aliphaticpolyesteramides (DE 19 753 534 A1, DE 19 800 698 A1, EP 0 820 698 A1),aliphatic and aromatic polyester urethanes (DE 19822979),polyhydroxyalkanoates, in particular polyhydroxybutyrates,polyhydroxyvalerates, casein (DE 4 309 528), polylactides andcopolylactides (EP 0 980 894 A1). The corresponding descriptions arehereby introduced as a reference and are deemed to be part of thedisclosure.

The above-stated materials may optionally be blended with furtherconventional auxiliary substances known to the person skilled in theart, preferably selected from the group consisting of glycerylmonostearate, semi-synthetic triglyceride derivatives, semi-syntheticglycerides, hydrogenated castor oil, glyceryl palmitostearate, glycerylbehenate, polyvinylpyrrolidone, gelatine, magnesium stearate, stearicacid, sodium stearate, talcum, sodium benzoate, boric acid and colloidalsilica, fatty acids, substituted triglycerides, glycerides,polyoxyalkylene glycols and the derivatives thereof.

If the dosage form according to the invention comprises a separationlayer (Z′), said layer, like the uncovered subunit (Y), may preferablyconsist of the above-stated materials described for the barrier layer.The person skilled in the art will understand that release of the activeingredient or of component (c) and/or (d) from the particular subunitmay be controlled by the thickness of the separation layer.

The dosage form according to the invention may comprise one or moreactive ingredients at least partially in controlled release form,wherein controlled release may be achieved with the assistance ofconventional materials and methods known to the person skilled in theart, for example by embedding the active ingredient in a controlledrelease matrix or by the application of one or more controlled releasecoatings. Active ingredient release must, however, be controlled suchthat the above-stated conditions are fulfilled in each case, for examplethat, in the event of correct administration of the dosage form, theactive ingredient or active ingredients are virtually completelyreleased before the optionally present component (c) and/or (d) canexert an impairing effect.

Controlled release from the dosage form according to the invention ispreferably achieved by embedding the active ingredient in a matrix. Theauxiliary substances acting as matrix materials control activeingredient release. Matrix materials may, for example, be hydrophilic,gel-forming materials, from which active ingredient release proceedsmainly by diffusion, or hydrophobic materials, from which activeingredient release proceeds mainly by diffusion from the pores in thematrix.

Physiologically acceptable, hydrophobic materials which are known to theperson skilled in the art may be used as matrix materials. Polymers,particularly preferably cellulose ethers, cellulose esters and/oracrylic resins are preferably used as hydrophilic matrix materials.Ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose,hydroxymethylcellulose, poly(meth)acrylic acid and/or the derivativesthereof, such as the salts, amides or esters thereof are veryparticularly preferably used as matrix materials.

Matrix materials prepared from hydrophobic materials, such ashydrophobic polymers, waxes, fats, long-chain fatty acids, fattyalcohols or corresponding esters or ethers or mixtures thereof are alsopreferred. Mono- or diglycerides of C12-C30 fatty acids and/or C12-C30fatty alcohols and/or waxes or mixtures thereof are particularlypreferably used as hydrophobic materials.

It is also possible to use mixtures of the above-stated hydrophilic andhydrophobic materials as matrix materials.

Component (C) and the optionally present component (D), which serve toachieve the breaking strength of at least 500 N which is necessaryaccording to the invention may furthermore also optionally serve asadditional matrix materials.

If the dosage form according to the invention is intended for oraladministration, it may also preferably comprise a coating which isresistant to gastric juices and dissolves as a function of the pH valueof the release environment. By means of this coating, it is possible toensure that the dosage form according to the invention passes throughthe stomach undissolved and the active ingredient is only released inthe intestines. The coating which is resistant to gastric juicespreferably dissolves at a pH value of between 5 and 7.5.

Corresponding materials and methods for the controlled release of activeingredients and for the application of coatings which are resistant togastric juices are known to the person skilled in the art, for examplefrom “Coated Pharmaceutical Dosage Forms—Fundamentals, ManufacturingTechniques, Biopharmaceutical Aspects, Test Methods and Raw Materials”by Kurt H. Bauer, K. Lehmann, Hermann P. Osterwald, Rothgang, Gerhart,1st edition, 1998, Medpharm Scientific Publishers. The correspondingliterature description is hereby introduced as a reference and is deemedto be part of the disclosure.

Method for Determining Breaking Strength

-   A) In order to verify whether a polymer may be used as component    (C), the polymer is pressed to form a tablet with a diameter of 10    mm and a height of 5 mm using a force of 150 N at a temperature    which at least corresponds to the softening point of the polymer and    is determined with the assistance of a DSC diagram of the polymer.    Using tablets produced in this manner, breaking strength is    determined with the apparatus described below in accordance with the    method for determining the breaking strength of tablets published in    the European Pharmacopoeia 1997, page 143-144, method no. 2.9.8. The    apparatus used for the measurement is a series 3300 universal    tester, single column benchtop model no. 3345 from Instron®, Canton,    Mass., USA. The clamping tool used is a pressure piston with a    diameter of 25 mm, which can be subjected to a load of up to 1 kN    (item no. 2501-3 from Instron®).    -   An Instron® universal tester, single column benchtop model no.        5543, with the above-stated clamping tool may also be used to        carry out the measurement.    -   The tablets deemed to be resistant to breaking under a specific        load include not only those which have not broken but also those        which may have suffered plastic deformation under the action of        the force.    -   Providing that the dosage form is in tablet form, breaking        strength may be determined using the same measurement method.

The following Examples illustrate the invention purely by way of exampleand without restricting the general concept of the invention.

EXAMPLES

Tramadol hydrochloride was used as the active ingredient in a series ofExamples. Tramadol hydrochloride was used, despite tramadol not being anactive ingredient which conventionally has abuse potential, because itis not governed by German narcotics legislation, so simplifying theexperimental work. Tramadol is moreover a member of the opioid classwith excellent water solubility.

Example 1

Per Complete Components tablet batch Tramadol hydrochloride 100 mg 100 gPolyethylene oxide, NF, MFI 200 mg 200 g (190° C. at 21.6 kg/10 min)<0.5 g MW 7 000 000 (Polyox WSR 303, Dow Chemicals) Total weight 300 mg300 g

Tramadol hydrochloride and polyethylene oxide powder were mixed in afree-fall mixer. A tabletting tool with top punch, bottom punch and diefor tablets with a diameter of 10 mm and a radius of curvature of 8 mmwas heated to 80° C. in a heating cabinet. 300 mg portions of the powdermixture were pressed with the heated tool, wherein pressure wasmaintained for at least 15 seconds by clamping the tabletting tool in avice.

The breaking strength of the tablets was determined with the statedapparatus in accordance with the stated method. The tablets did notbreak when exposed to a force of 500 N.

The tablet could not be comminuted using a hammer, nor with theassistance of a mortar and pestle.

In vitro release of the active ingredient from the preparation wasdetermined in a paddle stirrer apparatus in accordance with Pharm. Eur.The temperature of the release medium was 37° C. and the rotationalspeed of the stirrer 75 min⁻¹. At the beginning of the investigation,each tablet was placed in a 600 ml portion of artificial gastric juice,pH 1.2. After 30 minutes, the pH value was increased to 2.3 by additionof alkali solution, after a further 90 minutes to pH 6.5 and after afurther 60 minutes to pH 7.2. The released quantity of active ingredientpresent in the dissolution medium at each point in time was determinedby spectrophotometry.

Time Released quantity  30 min 15% 240 min 52% 480 min 80% 720 min 99%

Example 2

300 mg portions of the powder mixture from Example 1 were heated to 80°C. and in placed in the die of the tabletting tool. Pressing was thenperformed. The tablet exhibits the same properties such as the tablet inExample 1.

Example 3

Per Complete Raw material tablet batch Tramadol hydrochloride  50 mg 100g Polyethylene oxide, NF, 100 mg 200 g MW 7 000 000 (Polyox WSR 303, DowChemicals) Total weight 150 mg 300 g

Tramadol hydrochloride and the above-stated components were mixed in afree-fall mixer. A tabletting tool with top punch, bottom punch and diefor tablets with a diameter of 7 mm was heated to 80° C. in a heatingcabinet. 150 mg portions of the powder mixture were pressed with theheated tool, wherein pressure was maintained for at least 15 seconds byclamping the tabletting tool in a vice.

The breaking strength of the tablets was determined with the statedapparatus in accordance with the stated method. The tablets did notbreak when exposed to a force of 500 N.

In vitro release of the active ingredient was determined as in Example 1and was:

Time Released quantity  30 min 15% 240 min 62% 480 min 88% 720 min 99%

Example 4

Per Complete Raw material tablet batch Tramadol hydrochloride 100 mg 100g Polyethylene oxide, NF, 180 mg 180 g MW 7 000 000 (Polyox WSR 303, DowChemicals) Xanthan, NF  20 mg  20 g Total weight 300 mg 300 g

Tramadol hydrochloride, xanthan and polyethylene oxide were mixed in afree-fall mixer. A tabletting tool with top punch, bottom punch and diefor tablets with a diameter of 10 mm and a radius of curvature of 8 mmwas heated to 80° C. in a heating cabinet. 300 mg portions of the powdermixture were pressed with the heated tool, wherein pressure wasmaintained for at least 15 seconds by clamping the tabletting tool in avice.

The breaking strength of the tablets was determined with the statedapparatus in accordance with the stated method. The tablets did notbreak when exposed to a force of 500 N. The tablets did suffer a littleplastic deformation.

In vitro release of the active ingredient was determined as in Example 1and was:

Time Released quantity  30 min 14% 240 min 54% 480 min 81% 720 min 99%

The tablets could be cut up with a knife into pieces of an edge lengthof as small as approx. 2 mm. No further comminution proceeding as far aspulverisation was possible. When the pieces are combined with water, ahighly viscous gel is formed. Only with great difficulty could the gelbe pressed through a 0.9 mm injection cannula. When the gel was injectedinto water, the gel did not spontaneously mix with water, but remainedvisually distinguishable.

Example 5

Per Complete Raw material tablet batch Tramadol hydrochloride  50 mg 100g Polyethylene oxide, NF,  90 mg 180 g MW 7 000 000 (Polyox WSR 303, DowChemicals) Xanthan, NF  10 mg  20 g Total weight 300 mg 300 g

Tramadol hydrochloride, xanthan and polyethylene oxide were mixed in afree-fall mixer. A tabletting tool with a top punch, bottom punch anddie for oblong tablets 10 mm in length and 5 mm in width was heated to90° C. in a heating cabinet. 150 mg portions of the powder mixture werepressed with the heated tool, wherein pressure was maintained for atleast 15 seconds by clamping the tabletting tool in a vice.

The breaking strength of the tablets was determined with the statedapparatus in accordance with the stated method. The tablets did notbreak when exposed to a force of 500 N. The tablets did suffer a littleplastic deformation.

In vitro release of the active ingredient was determined as in Example 1and was:

Time Released quantity  30 min 22% 120 min 50% 240 min 80% 360 min 90%480 min 99%

The tablets could be cut up into pieces of an edge length of as small asapprox. 2 mm, but could not be pulverised. When the pieces are combinedwith water, a highly viscous gel is formed. Only with great difficultycould the gel be pressed through a 0.9 mm injection cannula. When thegel was injected into water, the gel did not spontaneously mix withwater, but remained visually distinguishable.

Example 6

A tablet with the following composition was produced as described inExample 1:

Per Per Components tablet batch Oxycodone hydrochloride  20.0 mg 0.240 gXanthan, NF  20.0 mg 0.240 g Polyethylene oxide, NF, MFI 110.0 mg 1.320g (190° C. at 21.6 kg/10 min) <0.5 g MW 7 000 000 (Polyox WSR 303, DowChemicals) Total weight 150.0 mg 1.800 g

Release of the active ingredient was determined as follows:

In vitro release of the active ingredient from the preparation wasdetermined in a paddle stirrer apparatus in accordance with Pharm. Eur.The temperature of the release medium was 37° C. and the rotationalspeed 75 rpm. The phosphate buffer, pH 6.8, described in DSP served asthe release medium. The quantity of active ingredient present in thesolvent at the particular time of testing was determined byspectrophotometry.

Time Mean  0 min    0%  30 min   17% 240 min   61% 480 min   90% 720 min101.1%

The breaking strength of the tablets was determined with the statedapparatus in accordance with the stated method. The tablets did notbreak when exposed to a force of 500 N.

The tablets could be cut up into pieces of an edge length of as small asapprox. 2 mm, but could not be pulverised. When the pieces are combinedwith water, a highly viscous gel is formed. Only with great difficultycould the gel be pressed through a 0.9 mm injection cannula. When thegel was injected into water, the gel did not spontaneously mix withwater, but remained visually distinguishable.

1. An abuse-proofed, thermoformed dosage form comprising one or moreactive ingredients with abuse potential (A) optionally together withphysiologically acceptable auxiliary substances (B), at least onesynthetic or natural polymer (C) and optionally at least one wax (D),wherein the dosage form exhibits a breaking strength of at least 500 N.2. A dosage form according to claim 1, which is in the form of a tablet.3. A dosage form according to claim 1, which is in multiparticulateform.
 4. A dosage form according to claim 1, wherein the polymer (C) isat least one polymer selected from the group consisting of polyethyleneoxide, polymethylene oxide, polypropylene oxide, polyethylene,polypropylene, polyvinyl chloride, polycarbonate, polystyrene,polyacrylate, copolymers and the mixtures thereof.
 5. A dosage formaccording to claim 1, wherein the polymer (C) has a molecular weight ofat least 0.5 million according to rheological measurements.
 6. A dosageform according to claim 5, wherein the molecular weight is 1-15 million.7. A dosage form according to claim 1, which comprises the wax (D) andthe wax (D) is at least one natural, semi-synthetic or synthetic waxwith a softening point of at least 60° C.
 8. A dosage form according toclaim 7, wherein the wax (D) is carnauba wax or beeswax.
 9. A dosageform according to claim 1, wherein the component(s) (C) is/are presentin quantities such that the dosage form has a breaking strength of atleast 500 N.
 10. A dosage form according to claim 1, wherein the activeingredient (A) is at least one active ingredient selected from the groupconsisting of opiates, opioids, tranquillisers, stimulants, barbituratesand further narcotics.
 11. A dosage form according to claim 1, whichadditionally comprises at least one of the following components a)-f):(a) at least one substance which irritates the nasal passages and/orpharynx, (b) at least one viscosity-increasing agent, which, with theassistance of a necessary minimum quantity of an aqueous liquid, forms agel with the extract obtained from the dosage form, which gel optionallyremains visually distinguishable when introduced into a further quantityof an aqueous liquid, c) at least one antagonist for the activeingredient or active ingredients with abuse potential, (d) at least oneemetic, (e) at least one dye as an aversive agent, (f) at least onebitter substance.
 12. A dosage form according to claim 11, wherein thecomponent (a) irritant substance causes burning, itching, an urge tosneeze, increased formation of secretions or a combination of at leasttwo of these stimuli.
 13. A dosage form according to claim 12, whereinthe component (a) irritant substance is based on one or moreconstituents of at least one hot substance drug.
 14. A dosage formaccording to claim 13, wherein the hot substance drug is at least onedrug selected from the group consisting of Allii sativi bulbus (garlic),Asari rhizoma cum herba (Asarum root and leaves), Calami rhizoma(calamus root), Capsici fructus (capsicum), Capsici fructus acer(cayenne pepper), Curcumae longae rhizoma (turmeric root), Curcumaexanthorrhizae rhizoma (Javanese turmeric root), Galangae rhizoma(galangal root), Myristicae semen (nutmeg), Piperis nigri fructus(pepper), Sinapis albae semen (erucae/white mustard seed), Sinapis nigrisemen (black mustard seed), Zedoariae rhizoma (zedoary root) andZingiberis rhizoma (ginger root).
 15. A dosage form according to claim13, wherein the constituent of the hot substance drug is ano-methoxy(methyl)phenol compound, an acid amide compound, a mustard oilor a sulfide compound or is derived from such a compound.
 16. A dosageform according to claim 13, wherein the constituent of the hot substancedrug is at least one constituent selected from the group consisting ofmyristicin, elemicin, isoeugenol, β-asarone, safrole, gingerols,xanthorrhizol, capsaicinoids, piperine, glucosinolates, and a compoundderived from these constituents.
 17. A dosage form according to claim11, wherein component (b) is at least one viscosity-increasing agentselected from the group consisting of microcrystalline cellulose with 11wt. % carboxymethylcellulose sodium (Avicel® RC 591),carboxymethylcellulose sodium (Blanose®, CMC-Na C300P®, FrimulsionBLC-5®, Tylose C300 P®), polyacrylic acid (Carbopol®980 NF, Carbopol®981), locust bean flour (Cesagum® LA-200, Cesagum® LID/150, Cesagum®LN-1), citrus pectin (Cesapectin® HM Medium Rapid Set), waxy maizestarch (C*Gel 04201®), sodium alginate (Frimulsion ALG (E401)®), guarflour (Frimulsion BM®, Polygum 26/1-75®), iota carrageen (FrimulsionD021®), karaya gum, gellan gum (Kelcogel F®, Kelcogel LT100®),galactomannan (Meyprogat 150®), tara bean flour (Polygum 43/1®),propylene glycol alginate (Protanal-Ester SD-LB®), sodium hyaluronate,apple pectin, pectin from lemon peel, sodium hyaluronate, tragacanth,tara gum (Vidogum SP 200®), fermented polysaccharide welan gum (K1A96)and xanthan gum (Xantural 180®).
 18. A dosage form according to claim11, wherein component (c) is at least one opiate or opioid antagonistselected from the group consisting of naloxone, naltrexone, nalmefene,nalid, nalmexone, nalorphine, naluphine and a correspondingphysiologically acceptable compound.
 19. A dosage form according toclaim 11, wherein component (c) is at least one neuroleptic stimulantantagonist.
 20. A dosage form according to claim 11, wherein component(d) emetic is based on one or more constituents of radix ipecacuanha(ipecac root) and/or is apomorphine.
 21. A dosage form according toclaim 11, wherein component (e) is at least one physiologicallyacceptable dye.
 22. A dosage form according to claim 11, whereincomponent (f) is at least one bitter substance selected from the groupconsisting of aromatic oils, fruit aroma substances, denatonium benzoateand mixtures thereof.
 23. A dosage form according to claim 11, whereinthe active ingredient or active ingredients (A) is/are spatiallyseparated from component (c) and/or (d) and/or (f), wherein the activeingredient or active ingredients (A) is/are optionally present in atleast one subunit (X) and components (c) and/or (d) and/or (f) is/arepresent in at least one subunit (Y), and, when the dosage form iscorrectly administered, components (c) and/or (d) and/or (f) fromsubunit (Y) do not exert their effect in the body and/or on taking. 24.A dosage form according to claim 1, which comprises at least one activeingredient at least partially in controlled release form.
 25. A dosageform according to claim 24, wherein each of the active ingredients withabuse potential (A) is present in a controlled release matrix.
 26. Adosage form according to claim 25, wherein component (C) and/orcomponent (D) also serve as a controlled release matrix material.
 27. Aprocess for the production of a dosage form according to claim 1,comprising: mixing components (A), (B), (C) and the optionally presentcomponent (D) and the optionally present components (a) to (f) to form aresultant mixture, and press-forming the resultant mixture, optionallyafter granulation, to yield the dosage form with preceding,simultaneous, or subsequent exposure to heat.
 28. A process according toclaim 27, wherein granulation is performed by means of a melt process.29. A dosage form obtainable by a process according to claim
 27. 30. Amethod of treating a therapeutic condition in a patient sufferingtherefrom, said method comprising administering to said patient a dosageform according to claim
 1. 31. The method according to claim 30, whereinthe therapeutic condition is pain.